AMG-397

Captor reports In oncology, where every innovation is of great importance, MCL-1 degraders have the potential to revolutionize the treatment. This is more than just a new class of drugs; it is a completely novel approach that could initiate a breakthrough, especially in cases of cancer resistant to available treatments. In this context, targeted protein degradation (TPD) can transform cancer treatment by eliminating MCL-1. The myeloid cell leukemia sequence 1 (MCL-1) protein plays a key role as a cell survival regulator, protecting cells from apoptosis - programmed cell death. In certain cancers, where MCL-1 production is excessive, its action promotes the uncontrolled growth of cancer cells. High levels of MCL-1 are particularly evident in acute myeloid leukemia (AML), where they correlate with the development of drug resistance to existing therapies, such as venetoclax treatment. MCL-1 is a well-understood and highly attractive therapeutic target due to its critical role in cancer cell survival. For this reason, many leading pharmaceutical companies, such as Amgen, AstraZeneca and Novartis, have recognized its potential and developed inhibitors - small molecules that block protein function. Some of these compounds, like AMG 397 and AZD5991, reached clinical trials. Unfortunately, due to unwanted side effects, further research into these drugs was suspended. The serious difficulties associated with previous studies on MCL-1-targeting therapeutics stem from the strategy itself, which focuses only on inhibiting the protein's activity while it still exists in excessive quantities within the cell. MCL-1 accumulation led to cardiotoxicity, which in clinical trials was evidenced by elevated troponin levels, markers of heart damage. Metabolic disturbances associated with MCL-1 excess led to the necrosis of cardiomyocytes - heart muscle cells. The accumulation of inactive MCL-1 also negatively affects the therapeutic outcome. Due to a positive feedback loop resulting from MCL-1 buildup, it becomes necessary to use increasingly higher doses of the drug to maintain the desired pharmacological effect. Additionally, MCL-1 has a complex biological role and belongs to the larger BCL-2 protein family. Cancer cells can develop compensatory mechanisms by activating other proteins from this family to avoid apoptosis after MCL-1 function is blocked. The activation of these mechanisms allows cancer cells to survive despite therapy. Developing MCL-1-targeting therapies faces many challenges. The solution to these difficulties is to find an alternative, tailored approach that fits the nature of the target. An approach based on targeted protein degradation allows for the complete removal of the target protein, unlike classical inhibitors which only block its activity and function. Instead of blocking, this new class of drugs - degraders - aims to eliminate proteins. This is an example of targeted protein degradation that uses the endogenous degradation system to effectively remove selected targets. The MCL-1 degraders developed by Captor Therapeutics are bifunctional molecules that act like a "magnet," attracting the MCL-1 protein to the cellular machinery responsible for its removal - the ubiquitin-proteasome system. As a result, the level of MCL-1 in cells is actively reduced, not just blocked, which is a more effective approach based on the precise elimination of the therapeutic target. In studies conducted on monkeys, a single dose led to the sustained degradation of MCL-1 in blood cells, with reduced protein levels maintained for at least 36 hours. Significantly, MCL-1 degraders did not cause cardiotoxicity, unlike inhibitors. This approach opens the door to safer and more effective treatment. MCL-1 degraders also have a promising safety and dosing profile. Toxicological studies on MCL-1 degraders confirm significantly lower cardiotoxicity compared to traditional inhibitors, while having a strong cytotoxic effect that eliminates cancer cells without affecting healthy heart cells. The low troponin-I levels in monkeys after degrader administration is strong evidence for cardiovascular safety. Furthermore, the prolonged pharmacodynamic effect - maintaining low MCL-1 levels for over 36 hours - suggests that patients will not need to take the drug daily. In the future, clinical trials may show dosing could be once or twice a week, which is a significant advantage for patients. In this case, targeted protein degradation technology has opened the prospect of developing new drugs and therapies that could revolutionize cancer treatment. The market opportunities for MCL-1 degraders are promising. The main therapeutic indication is blood cancer, particularly acute myeloid leukemia (AML). However, the use of MCL-1 degraders has a much broader scope and may include the treatment of solid tumors, such as non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC), which currently accounts for 10-15% of breast cancer cases. Analyses indicate that over the last decade, the number of clinical trials for hematological cancers has increased by 30%, with more than 450 started in 2024 alone. Solid tumors account for as much as 79% of all oncology trials initiated in 2024. The size of the market for blood cancer therapies, including AML, is estimated at $114 billion by 2030. Meanwhile, for solid tumor therapies, including lung and breast cancer, it is expected to reach $406 billion by 2035. The global market for oncology therapy expenditures is projected to grow at a compound annual growth rate (CAGR) of 9.5–12.5% over the next 5 years. This data shows that the potential for development in this area is enormous, and the introduction of MCL-1 degraders to the market could be crucial for further progress in oncological therapy. In the field of cancer therapy, innovative drugs targeting specific molecular mechanisms play a key role in redefining treatment standards. Although there are some clinical limitations and side effects of currently used solutions, the market introduction of existing therapies has been associated with both a medical breakthrough and financial success. Venetoclax (Venclexta), used to treat AML, currently has annual sales of nearly $1 billion. For non-small cell lung cancer, Merck's drug Keytruda (Pembrolizumab), targeting PD-1 (programmed death receptor-1), reached sales of over $20 billion in 2023. Trodelvy (Sacituzumab govitecan) from Gilead, used in triple-negative breast cancer (TNBC), is at the $1 billion level. It is worth noting that for years, triple-negative breast cancer was a subtype with the worst prognosis, but thanks to therapeutic progress, the situation for patients is improving. The presence of major classes of compounds used in these therapies, such as monoclonal antibodies and inhibitors, is important for treatment efficacy, but it is not the last word in the development of medicine in this field. Despite the advanced oncology therapies currently available, the market is still waiting for new, more effective approaches that will minimize risk and improve treatment outcomes. All this shows that the future belongs to innovative, safe, and targeted therapies. With their unique mechanism of action and promising profile, MCL-1 degraders, being a first-in-class drug, have a real chance to become a breakthrough in oncology.